It is estimated by the World Health Organization that 18 million people suffer from Alzheimer's disease worldwide (Vas et al. 2001). In the Netherlands, approximately 250,000 people have the Alzheimer's disease. The problem is expanding with increasing average age of the population. Care for a patient in a nursing home is estimated to cost 30,000-60,000 per year (McDonnell et al. 2001). Vaccination would be cost-effective.
Alzheimer's disease is a conformational neurodegenerative disorder (Sadowski & Wisniewski 2004, Blennow et al. 2006, Editorials Nature Med. 2006). A characteristic of the disease is formation of plaques in the brain or in brain blood vessels. These plaques originate from a neuronal membrane-bound protein, the amyloid precursor protein. An α-helical fragment of 38-43 (typically 42) amino acid residues is cleaved enzymatically from the protein thus forming a peptide called “soluble Aβ β probably first adopts an extended conformation and is present in all body fluids. If soluble Aβ reaches a high concentration, it will undergo conformational changes and form aggregates. A plethora of aggregates has been found in vitro or in vivo, including multiple monomer conformers, different types of oligomers, Aβ-derived diffusable ligands, protofibrils, fibrils, and spheroids (adopted from Klein et al. 2004). Fibrillar Aβ has a cross-beta spine structure (Sawaya et al. 2007) and is eventually deposited in the brain to form the neurodegenerative plaques.
Immunization of transgenic mice (Schenk et al. 1999) and human patients in a phase I clinical trial (Hock et al. 2002) with a suspension of “pre-aggregated” Aβ 1-42 seemed to be beneficial. Antibodies in human immune sera recognized plaques, Aβ deposits and β-amyloid in brain blood vessels. The antibodies did not recognize the amyloid precursor protein or soluble Aβ.
A disadvantage of the “pre-aggregated” Aβ 1-42 suspension is that physical properties of this material are ill-defined. However, a far more serious problem was induction of meningoencephalitis as a vaccine-related side effect in 6% of the patients during a phase II clinical trial (Check 2002, Gilman et al. 2005). This side effect is caused by a cellular inflammatory reaction, attributed to a Th1 cellular response to epitopes located in the central and C-terminal part of Aβ 1-42 (McLaurin et al. 2002, Gelinas et al. 2004).
It has been demonstrated that beneficial antibodies induced by Aβ 1-42 are directed against the N-terminus (McLaurin et al. 2002, (Lee et al. 2005). It was therefore proposed to use C-terminally truncated Aβ peptides as immunogens (Sigurdsson et al. 2004, Lemere et al. 2006, Gevorkian et al. 2004, Lemere et al. 2007). Such short peptides are poorly immunogenic. In order to increase the immunogenicity, multiple copies of the peptide should be coupled to non-immunogenic carriers (with the aim of inducing IgM) or to carriers providing heterologous T cell epitopes (Agadjanyan et al. 2005, Ghochikyan et al. 2006, Maier et al. 2006, (Movsesyan et al. 2008)). In neither of these conjugates the peptide is expected to adopt the conformation of residues 4-10 as exposed by the β amyloid oligomers or pre-fibrils. Thus, antibodies induced with truncated peptide conjugates are expected to be weakly specific for the oligomers or pre-fibrils.
Therefore, there is still a need for an efficient medicament, preferably a vaccine against the Alzheimer's disease. The present invention provides an improved vaccine, which does not have all the drawbacks of existing vaccines: less to no toxicity and still able to induce an effective antibody response for immunization. The vaccine proposed in the present invention is a new analogue of the β-amyloid peptide.